Is PAK1 p.Pro462Ser (c.1384C>T) pathogenic?

PAK1 p.Pro462Ser (c.1384C>T) is classified Uncertain significance in PAK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-01). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1.

How common is PAK1 p.Pro462Ser (c.1384C>T) in the general population?

PAK1 p.Pro462Ser (c.1384C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PAK1 p.Pro462Ser (c.1384C>T)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

PAK1 p.Pro462Ser

c.1384C>T · rs2539943040 · VCV2500399

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic · top 10% in PAK1
REVEL	0.633	indeterminate
SaProt	LLR -15.98	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 13 kb · p 1.6e-12 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PAK1
Protein: p.Pro462Ser
Coding: c.1384C>T
MANE Select: NM_002576
dbSNP: rs2539943040
Type: single nucleotide variant
Location: chr11:77336115 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 73.90 · 41 PDB
Residue 462: the protein kinase domain

Full PAK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PAK1 p.Ile476Thr Pathogenic/Likely pathogenic ★★ same type
PAK1 p.Leu470Arg Likely pathogenic ★★ same type
PAK1 p.Met143Thr Likely pathogenic ★★ same type
PAK1 p.Pro121Leu Pathogenic ★★ same type
PAK1 p.Pro121Ser Pathogenic/Likely pathogenic ★★ same type
PAK1 p.Ala524Pro Uncertain significance ★★ ⚠ same type
PAK1 p.Arg215Trp Uncertain significance ★★ ⚠ same type
PAK1 p.Arg258Ter Uncertain significance ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pak1-p-pro462ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown